Identification of KIF21A mutations as a rare cause of congenital fibrosis of the extraocular muscles type 3 (CFEOM3).

PURPOSE. Three congenital fibrosis of the extraocular muscles phenotypes (CFEOM1-3) have been identified. Each represents a specific form of paralytic strabismus characterized by congenital restrictive ophthalmoplegia, often with accompanying ptosis. It has been demonstrated that CFEOM1 results from mutations in KIF21A and CFEOM2 from mutations in PHOX2A. This study was conducted to determine the incidence of KIF21A and PHOX2A mutations among individuals with the third CFEOM phenotype, CFEOM3. METHODS. All pedigrees and sporadic individuals with CFEOM3 in the authors' database were identified, whether the pedigrees were linked or consistent with linkage to the FEOM1, FEOM2, and/or FEOM3 loci was determined, and the appropriate pedigrees and the sporadic individuals were screened for mutations in KIF21A and PHOX2A. RESULTS. Twelve CFEOM3 pedigrees and 10 CFEOM3 sporadic individuals were identified in the database. The structures of eight of the pedigrees permitted the generation of meaningful linkage data. KIF21A was screened in 17 probands, and mutations were identified in two CFEOM3 pedigrees. One pedigree harbored a novel mutation (2841G-->A, M947I) and one harbored the most common and recurrent of the CFEOM1 mutations identified previously (2860C-->T, R954W). None of CFEOM3 pedigrees or sporadic individuals harbored mutations in PHOX2A. CONCLUSIONS. The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 and that KIF21A mutations can be nonpenetrant. Although KIF21A is the first gene to be associated with CFEOM3, the results imply that mutations in the unidentified FEOM3 gene are the more common cause of this phenotype

Tribute to Professor David Bruck

A tribute to Professor David I. Bruck, who served on the faculty of the Washington and Lee University School of Law from 2004 to 2020. Bruck directed W&L\u27s death penalty defense clinic, the Virginia Capital Case Clearinghouse, also known as VC3 . He became Professor of Law, Emeritus in 2020

The cost-effectiveness of small-quantity lipid-based nutrient supplements for prevention of child death and malnutrition and promotion of healthy development: modeling results for Uganda

Abstract Objective: Recent meta-analyses demonstrate that small-quantity lipid-based nutrient supplements (SQ-LNS) for young children significantly reduce child mortality, stunting, wasting, anemia and adverse developmental outcomes. Cost considerations should inform policy decisions. We developed a modeling framework to estimate the cost and cost-effectiveness of SQ-LNS and apply the framework in the context of rural Uganda. Design: We adapted costs from a costing study of micronutrient powder (MNP) in Uganda, and based effectiveness estimates on recent meta-analyses and Uganda-specific estimates of baseline mortality and the prevalence of stunting, wasting, anemia, and developmental disability. Setting: Rural Uganda. Participants: Not applicable. Results: Providing SQ-LNS daily to all children in rural Uganda (>1 million) for 12 months (from 6-18 months of age) via the existing Village Health Team system would cost ∼$52 per child (2020 US dollars), or ∼$58.7 million annually. Annually, SQ-LNS could avert an average of >242,000 disability adjusted life years (DALYs) as a result of preventing 3,689 deaths, >160,000 cases of moderate or severe anemia, and ∼6,000 cases of developmental disability. The estimated cost per DALY averted is $242. Conclusions: In this context, SQ-LNS may be more cost-effective than other options such as MNP or the provision of complementary food, although the total cost for a program including all age-eligible children would be high. Strategies to reduce costs, such as targeting to the most vulnerable populations and the elimination of taxes on SQ-LNS, may enhance financial feasibility

The Society for Immunotherapy of Cancer statement on best practices for multiplex immunohistochemistry (IHC) and immunofluorescence (IF) staining and validation.

OBJECTIVES: The interaction between the immune system and tumor cells is an important feature for the prognosis and treatment of cancer. Multiplex immunohistochemistry (mIHC) and multiplex immunofluorescence (mIF) analyses are emerging technologies that can be used to help quantify immune cell subsets, their functional state, and their spatial arrangement within the tumor microenvironment. METHODS: The Society for Immunotherapy of Cancer (SITC) convened a task force of pathologists and laboratory leaders from academic centers as well as experts from pharmaceutical and diagnostic companies to develop best practice guidelines for the optimization and validation of mIHC/mIF assays across platforms. RESULTS: Representative outputs and the advantages and disadvantages of mIHC/mIF approaches, such as multiplexed chromogenic IHC, multiplexed immunohistochemical consecutive staining on single slide, mIF (including multispectral approaches), tissue-based mass spectrometry, and digital spatial profiling are discussed. CONCLUSIONS: mIHC/mIF technologies are becoming standard tools for biomarker studies and are likely to enter routine clinical practice in the near future. Careful assay optimization and validation will help ensure outputs are robust and comparable across laboratories as well as potentially across mIHC/mIF platforms. Quantitative image analysis of mIHC/mIF output and data management considerations will be addressed in a complementary manuscript from this task force

Divergence of the Yeast Transcription Factor FZF1 Affects Sulfite Resistance

Changes in gene expression are commonly observed during evolution. However, the phenotypic consequences of expression divergence are frequently unknown and difficult to measure. Transcriptional regulators provide a mechanism by which phenotypic divergence can occur through multiple, coordinated changes in gene expression during development or in response to environmental changes. Yet, some changes in transcriptional regulators may be constrained by their pleiotropic effects on gene expression. Here, we use a genome-wide screen for promoters that are likely to have diverged in function and identify a yeast transcription factor, FZF1, that has evolved substantial differences in its ability to confer resistance to sulfites. Chimeric alleles from four Saccharomyces species show that divergence in FZF1 activity is due to changes in both its coding and upstream noncoding sequence. Between the two closest species, noncoding changes affect the expression of FZF1, whereas coding changes affect the expression of SSU1, a sulfite efflux pump activated by FZF1. Both coding and noncoding changes also affect the expression of many other genes. Our results show how divergence in the coding and promoter region of a transcription factor alters the response to an environmental stress

Peace and Justice through a Feminist Lens: Gender Justice and the Women’s Court for the Former Yugoslavia

Post-conflict interventions to ‘deal with’ violent pasts have moved from exception to global norm. Early efforts to achieve peace and justice were critiqued as ‘gender-blind’—for failing to address sexual and gender-based violence, and neglecting the gender-specific interests and needs of women in transitional settings. The advent of UN Security Council resolutions on ‘Women, Peace and Security’ provided a key policy framework for integrating both women and gender issues into transitional justice processes and mechanisms. Despite this, gender justice and equality in (post-)conflict settings remain largely unachieved. This article explores efforts to attain gender-just peace in post-conflict Bosnia and Herzegovina (BiH). It critically examines the significance of a recent ‘bottom-up’ truth-telling project—the Women’s Court for the former Yugoslavia—as a locally engaged approach to achieving justice and redress for women impacted by armed conflict. Drawing on participant observation, documentary analysis, and interviews with women activists, the article evaluates the successes and shortcomings of responding to gendered forms of wartime violence through truth-telling. Extending Nancy Fraser’s tripartite model of justice to peacebuilding contexts, the article advances notions of recognition, redistribution and representation as crucial components of gender-just peace. It argues that recognizing women as victims and survivors of conflict, achieving a gender-equitable distribution of material and symbolic resources, and enabling women to participate as agents of transitional justice processes are all essential for transforming the structural inequalities that enable gender violence and discrimination to materialize before, during, and after conflict

Early life child micronutrient status, maternal reasoning, and a nurturing household environment have persistent influences on child cognitive development at age 5 years: Results from MAL-ED

Background: Child cognitive development is influenced by early-life insults and protective factors. To what extent these factors have a long-term legacy on child development and hence fulfillment of cognitive potential is unknown. Objective: The aim of this study was to examine the relation between early-life factors (birth to 2 y) and cognitive development at 5 y. Methods: Observational follow-up visits were made of children at 5 y, previously enrolled in the community-based MAL-ED longitudinal cohort. The burden of enteropathogens, prevalence of illness, complementary diet intake, micronutrient status, and household and maternal factors from birth to 2 y were extensively measured and their relation with the Wechsler Preschool Primary Scales of Intelligence at 5 y was examined through use of linear regression. Results: Cognitive T-scores from 813 of 1198 (68%) children were examined and 5 variables had significant associations in multivariable models: mean child plasma transferrin receptor concentration (β: −1.81, 95% CI: −2.75, −0.86), number of years of maternal education (β: 0.27, 95% CI: 0.08, 0.45), maternal cognitive reasoning score (β: 0.09, 95% CI: 0.03, 0.15), household assets score (β: 0.64, 95% CI: 0.24, 1.04), and HOME child cleanliness factor (β: 0.60, 95% CI: 0.05, 1.15). In multivariable models, the mean rate of enteropathogen detections, burden of illness, and complementary food intakes between birth and 2 y were not significantly related to 5-y cognition. Conclusions: A nurturing home context in terms of a healthy/clean environment and household wealth, provision of adequate micronutrients, maternal education, and cognitive reasoning have a strong and persistent influence on child cognitive development. Efforts addressing aspects of poverty around micronutrient status, nurturing caregiving, and enabling home environments are likely to have lasting positive impacts on child cognitive development.publishedVersio

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead